Long Term Outcomes of Pediatric Patients with Sickle Cell Disease Who Underwent a Reduced Intensity T Cell Depleted Haploidentical Transplantation

Allogeneic hematopoietic stem cell transplant (HCT) is a curative therapy for sickle cell disease (SCD).  However, majority of patients lack a matched sibling or unrelated donor.  The use of a partially matched related donor would provide donors for majority of the patients.  We report the results of 8 consecutive pediatric patients with SCD who had a prior stroke, who underwent a T cell depleted HLA-haploidentical HCT using a reduced intensity conditioning regimen without total body irradiaiton.  The median age was 7±5 yrs. (4-17) with the median follow up of 7±3 yrs (3-9).  The first 3 patients received fludarabine (150-200 mg/m²), thiotepa (10mg/kg), targeted busulfan (900 ng/ml for 4 d), rabbit antithymocyte globulin (rATG) (10mg/kg x 3 d), and OKT3 (0.1mg/kg maximum over d +1 to +20).  The subsequent 5 patients received busulfan (900ng/ml x 4 d), thiotepa (10mg/kg), cyclophosphamide (200 mg/kg) and OKT3 (0.1mg/kg max on d-10 to +17) as well as mycophenolate mofetil for graft versus host (GVHD) prophylaxis.  The product consisted of a CD34⁺ selected product infused on d0 and a CD3⁺ depleted product infused on d+1.  The infused products had a mean total nucleated cell (TNC) of 450±680 x 10⁶ kg (10-1890), CD34⁺ cells of 25.4±16.3 x 10⁶/kg (6-57) and CD3⁺ cells of 0.07±0.07 x 10⁶/kg (0.006-0.168).  All 8 patients achieved donor engraftment with a median of 12 d (10-14). Donor engraftment was maintained in 5 patients, with one patient requiring a second stem cell infusion. The median time to rejection for the 4 patients was 30 d (22-44) after HSCT.  Of the 5 engrafted patients, 4 patients developed acute GVHD (3 with grade I-II and 1 with Grade III).  Of the 5 engrafted patients, 3 developed chronic GVHD  (1 with limited and 2 with extensive). The 2 patients with extensive GVHD died of complication of GVHD.  The 3 surviving patients have been transfusion independent with no evidence of SCD related complications. Indices of hemolysis decreased after HCT with decreased reticulocyte count, bilirubin and LDH. The median hemoglobin increased from 9.6 ± 0.6 to 13.6 ± 2. Renal and cardiac were stable after HCT.  MRI showed no new infarct or vessel occlusion.  In summary, 3 patients survived free of SCD, 2 engrafted but died of complications from GVHD and 3 had recurrent SCD after graft rejection. Despite good outcomes in 3 of the 8 patients, rejection, chronic GVHD and transplant related mortality were significant problems.  Recently, Bolaños-Meade et al published the result of haploidentical HCT for SCD using post-transplant cyclophosphamide.  Both regimens encountered graft failure, however GVHD and mortality was not as prevalent as our report.  Though limited, our data suggest that for patients with SCD, graft-versus-host disease prophylaxis after haploidentical HCT with high dose cyclophosphamide may be a safer regimen and further studies are warranted.